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Mycotoxins are secondary metabolites of fungi that cause severe damage to agricultural products and food in the food supply chain. These detrimental pollutants have been directly linked with poor socioeconomic patterns and human health issues. Among the natural micropollutants, ochratoxin A (OTA) and deoxynivalenol (DON) are widely distributed in food materials. The primary occurrence of these mycotoxins is reported in almost all cereal grains and fresh agro-products. Both mycotoxins have shown harmful effects, such as nephrotoxic, hepatotoxic, and genotoxic effects, in humans due to their complex structural formation during the degradation/acetylation reaction. In addition, improper preharvest, harvest, and postharvest handling tend to lead to the formation of OTA and DON in various food commodities, which allows different harmful fungicides in practice. Therefore, this review provides more insight into the distribution and toxicity of OTA/DON in the food matrix and human health. Furthermore, the interactive effects of OTA/DON with co-contaminated organic and inorganic compounds are discussed. Finally, international regulation and mitigation strategies for detoxication are critically evaluated to meet food safety and good agriculture practices.